Body Compartment Pharmacokinetics of Anti-retroviral Agents That May be Considered for Future On-demand Peri-exposure HIV Prophylaxis Regimens

This study is being conducted to determine if the uptake of anti-HIV medication, called Genvoya®, at different time-frames, is different at several body sites, including mucosal tissues. This medication might be considered for on-demand PEP regimens in the future.

Study Overview

• Status: Completed
• Conditions: HIV/AIDS
• Intervention / Treatment: Drug: Genvoya

Detailed Description

Men who have sex with men (MSM) continue to be disproportionately affected by HIV. The majority of MSM acquire HIV after exposure to the rectal mucosa through unprotected receptive anal intercourse. Post-exposure-prophylaxis (PEP) is an intervention that is used to prevent HIV infection soon (72 hours) after a potential exposure. HIV-negative people with a possible exposure to HIV are instructed to take 28 days of a combination anti-HIV medication regimen, Truvada® + Raltegravir.

This study is being conducted to determine if the uptake of another anti-HIV medication, called Genvoya®, at different time-frames, is different at several body sites, including mucosal tissues. This medication might be considered for on-demand PEP regimens in the future.

• Study Type: Interventional
• Enrollment (Actual): 41
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Hope Clinic

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 49 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Male

Description

Inclusion Criteria:

1. HIV-negative man who reports receptive anal sex with another man in the last 6 months
2. Aged 18-49 years
3. Not currently taking PrEP and no plans to initiate during study
4. Not currently taking PEP
5. Able to provide informed consent in English
6. No plans for relocation in the next 3 months
7. Willing to undergo peripheral blood, penile swabs, urine, and rectal biopsy sampling
8. Willing to use study products as directed
9. Willing to abstain from receptive anal intercourse 3 days prior to starting study product and for the duration of the study and for 7 days after any rectal biopsy procedure.
10. Hepatitis B surface antigen (HBsAg) must be negative (screening lab test)
11. Creatine clearance >60 ml/min

Exclusion Criteria:

1. History of inflammatory bowel disease or other inflammatory, infiltrative, infectious or vascular condition involving the lower gastrointestinal tract that, in the judgment of the investigators, may be worsened by study procedures or may significantly distort the anatomy of the distal large bowel
2. Currently infected with hepatitis virus and/ or have liver disease
3. Current or chronic history of kidney disease

4. Significant laboratory abnormalities at baseline visit, including but not limited to:

   1. Hgb ≤ 10 g/dL
   2. Partial thromboplastin time (PTT) > 1.5x upper limit of normal (ULN) or international normalized ratio (INR) > 1.5x ULN
   3. Platelet count <100,000
   4. Creatinine clearance <60
   5. HBsAg reactive

5. Any known medical condition that, in the judgment of the investigators, increases the risk of local or systemic complications of endoscopic procedures or pelvic examination, including but not limited to:

   1. Uncontrolled or severe cardiac arrhythmia
   2. Recent major abdominal, cardiothoracic, or neurological surgery
   3. History of uncontrolled bleeding diathesis
   4. History of colonic, rectal, or vaginal perforation, fistula, or malignancy
   5. History or evidence on clinical examination of ulcerative, suppurative, or proliferative lesions of the anorectal mucosa, or untreated sexually transmitted disease with mucosal involvement

6. Continued need for, or use during the 14 days prior to enrollment, of the following medications:

   1. Aspirin or more than 4 doses of NSAIDs
   2. Warfarin, heparin (low-molecular weight or unfractionated), platelet aggregation inhibitors, or fibrinolytic agents
   3. Any form of rectally administered agent besides lubricants or douching used for sexual intercourse

7. Continued need for, or use during the 90 days prior to enrollment, of the following medications:

   1. Systemic immunomodulatory agents
   2. Supraphysiologic doses of steroids (short course steroids less than 7 days duration, allowable at the discretion of the investigators)
   3. Experimental medications, vaccines, or biologicals
8. Intent to use HIV antiretroviral pre/post-exposure prophylaxis (PrEP or PEP) during the study, outside of the study procedures
9. Symptoms of an untreated rectal sexually transmitted infection (e.g. rectal pain, discharge, bleeding, etc.)
10. Current use of hormonal therapy
11. Any other clinical condition or prior therapy that, in the opinion of the investigator, would make the patient unsuitable for the study or unable to comply with the study requirements.
12. Participants taking potent inhibitors (e.g. itraconazole, diltiazem) or inducers (e.g. rifampin, phenytoin) of the CYP3A4 enzyme that also metabolizes Genvoya will be excluded from the study

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

5

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
No Intervention: Pre-drug; Participants enrolled in the pre-drug arm will not receive any drug. At visit 2, they will undergo blood, urine, penile swab, cheek swab, rectal swab and rectal biopsy collection.
Experimental: Genvoya - 2 and 48 hours specimen collection; Specimen collection 2 hours after taking the medication in the clinic (visit 4), and 48 hours after taking the medication in the clinic (visit 5).	Drug: Genvoya; Genvoya is a fixed-dose combination anti-retroviral drug containing tenofovir alafenamide (TAF), emtricitabine (FTC), elvitegravir (EVG), and cobicistat. At the second study visit, participants will be provided with a single dose of Genvoya, and instructed to take the dose at home with documentation by digital, time-stamped photo or video. At the third study visit, which will occur 24 hours after home dosing, participants will be given another single dose of Genvoya at the clinic.; Other Names: Cobicistat/Elvitegravir/Emtricitabine/Tenofovir alafenamide
Experimental: Genvoya - 4 and 72 hours specimen collection; Specimen collection 4 hours after taking the medication in the clinic (visit 4), and 72 hours after taking the medication in the clinic (visit 5).	Drug: Genvoya; Genvoya is a fixed-dose combination anti-retroviral drug containing tenofovir alafenamide (TAF), emtricitabine (FTC), elvitegravir (EVG), and cobicistat. At the second study visit, participants will be provided with a single dose of Genvoya, and instructed to take the dose at home with documentation by digital, time-stamped photo or video. At the third study visit, which will occur 24 hours after home dosing, participants will be given another single dose of Genvoya at the clinic.; Other Names: Cobicistat/Elvitegravir/Emtricitabine/Tenofovir alafenamide
Experimental: Genvoya - 24 and 96 hours specimen collection; Specimen collection 24 hours after taking the medication in the clinic (visit 4), and 96 hours after taking the medication in the clinic (visit 5).	Drug: Genvoya; Genvoya is a fixed-dose combination anti-retroviral drug containing tenofovir alafenamide (TAF), emtricitabine (FTC), elvitegravir (EVG), and cobicistat. At the second study visit, participants will be provided with a single dose of Genvoya, and instructed to take the dose at home with documentation by digital, time-stamped photo or video. At the third study visit, which will occur 24 hours after home dosing, participants will be given another single dose of Genvoya at the clinic.; Other Names: Cobicistat/Elvitegravir/Emtricitabine/Tenofovir alafenamide
Experimental: Genvoya - Single time point specimen collection; Specimen collection 8 hours after taking the medication in the clinic (visit 4).	Drug: Genvoya; Genvoya is a fixed-dose combination anti-retroviral drug containing tenofovir alafenamide (TAF), emtricitabine (FTC), elvitegravir (EVG), and cobicistat. At the second study visit, participants will be provided with a single dose of Genvoya, and instructed to take the dose at home with documentation by digital, time-stamped photo or video. At the third study visit, which will occur 24 hours after home dosing, participants will be given another single dose of Genvoya at the clinic.; Other Names: Cobicistat/Elvitegravir/Emtricitabine/Tenofovir alafenamide

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Plasma Concentration of Tenofovir (TFV)	Median drug concentrations of the TFV component of Genvoya were determined at baseline and at each of the protocol specified follow-up time points. Concentrations below the limit of quantification (LOQ) are assigned a value of zero.	Baseline, and 2, 4, 8, 24, 48, 72, 96 hours after taking the second dose of medication
Plasma Concentration of Emtricitabine (FTC)	Median drug concentrations of the FTC component of Genvoya were determined at baseline and at each of the protocol specified follow-up time points. Concentrations below the limit of quantification (LOQ) are assigned a value of zero.	Baseline, and 2, 4, 8, 24, 48, 72, 96 hours after taking the second dose of medication
Plasma Concentration of Elvitegravir (EVG)	Median drug concentrations of the EVG component of Genvoya were determined at baseline and at each of the protocol specified follow-up time points. Concentrations below the limit of quantification (LOQ) are assigned a value of zero.	Baseline, and 2, 4, 8, 24, 48, 72, 96 hours after taking the second dose of medication

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Peripheral Blood Mononuclear Cell (PBMC) Concentration of Tenofovir-diphosphate (TFV-DP)	A peripheral blood mononuclear cell (PBMC) is any peripheral blood cell having a round nucleus: lymphocytes (T cells, B cells, natural killer (NK) cells) and monocytes. Median drug concentrations were determined at baseline and at each of the protocol specified follow-up time points. Concentrations below the limit of quantification (LOQ) are assigned a value of zero.	Baseline, and 2, 4, 8, 24, 48, 72, 96 hours after taking the second dose of medication
Peripheral Blood Mononuclear Cell (PBMC) Concentration of Emtricitabine-triphosphate (FTC-TP)	A peripheral blood mononuclear cell (PBMC) is any peripheral blood cell having a round nucleus: lymphocytes (T cells, B cells, NK cells) and monocytes. Median drug levels were determined at baseline and at each of the protocol specified follow-up time points. Concentrations below the limit of quantification (LOQ) are assigned a value of zero.	Baseline, and 2, 4, 8, 24, 48, 72, 96 hours after taking the second dose of medication

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Rectal Tissue Concentration of Tenofovir (TFN)	Median drug concentrations in rectal tissue of the TFN component of Genvoya were determined at baseline and at each of the protocol specified time points. Concentrations below the limit of quantification (LOQ) are assigned a value of zero.	Baseline, and 2, 4, 8, 24, 48, 72, 96 hours after taking the second dose of medication
Rectal Tissue Concentration of Emtricitabine (FTC)	Median drug concentrations in rectal tissue of the FTC component of Genvoya were determined at baseline and at each of the protocol specified time points. Concentrations below the limit of quantification (LOQ) are assigned a value of zero.	Baseline, and 2, 4, 8, 24, 48, 72, 96 hours after taking the second dose of medication
Rectal Tissue Concentration of Elvitegravir (EVG)	Median drug concentrations in rectal tissue of the EVG component of Genvoya were determined at baseline and at each of the protocol specified time points. Concentrations below the limit of quantification (LOQ) are assigned a value of zero.	Baseline, and 2, 4, 8, 24, 72, 96 hours after taking the second dose of medication
Rectal Tissue Concentration of Tenofovir-diphosphate (TFV-DP)	Median drug concentrations of TFV-DP in rectal tissue were determined at baseline and at each of the protocol specified follow-up time points. Concentrations below the limit of quantification (LOQ) are assigned a value of zero.	Baseline, and 2, 4, 8, 24, 48, 72, 96 hours after taking the second dose of medication
Rectal Tissue Concentration of Emtricitabine-triphosphate (FTC-TP)	Median drug concentrations of FTC-TP in rectal tissue were determined at baseline and at each of the protocol specified follow-up time points. Concentrations below the limit of quantification (LOQ) are assigned a value of zero.	Baseline, and 2, 4, 8, 24, 48, 72, 96 hours after taking the second dose of medication

Collaborators and Investigators

• Sponsor: Emory University
• Collaborators: Centers for Disease Control and Prevention
• Investigators: Principal Investigator: Colleen Kelley, MD, Emory University

Study record dates

Study Major Dates

• Study Start (Actual): March 13, 2019
• Primary Completion (Actual): September 20, 2019
• Study Completion (Actual): September 20, 2019

Study Registration Dates

• First Submitted: June 4, 2019
• First Submitted That Met QC Criteria: June 5, 2019
• First Posted (Actual): June 6, 2019

Study Record Updates

• Last Update Posted (Actual): August 13, 2021
• Last Update Submitted That Met QC Criteria: July 20, 2021
• Last Verified: July 1, 2021

More Information

Terms related to this study

• Keywords: HIV; Pharmacokinetics; MSM; Anti-retrovirals; Peri-exposure HIV prophylaxis
• Additional Relevant MeSH Terms: RNA Virus Infections; Virus Diseases; Infections; Blood-Borne Infections; Communicable Diseases; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; Immunologic Deficiency Syndromes; Immune System Diseases; Slow Virus Diseases; HIV Infections; Acquired Immunodeficiency Syndrome; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Reverse Transcriptase Inhibitors; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Anti-HIV Agents; Anti-Retroviral Agents; Cytochrome P-450 CYP3A Inhibitors; Cytochrome P-450 Enzyme Inhibitors; Integrase Inhibitors; Tenofovir; Emtricitabine; Emtricitabine tenofovir alafenamide; Cobicistat; Elvitegravir, Cobicistat, Emtricitabine, Tenofovir Disoproxil Fumarate Drug Combination; Elvitegravir
• Other Study ID Numbers: IRB00108386

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD Plan Description: Individual participant data that underlie the results reported in this article, after de-identification (e.g., text, tables, figures, and appendices), will be available. The study protocol will be available. Data will become available Beginning 9 months and ending at 36 months following publication to researchers who provide a methodologically sound proposal.
• IPD Sharing Time Frame: Data will become available beginning 9 months and ending at 36 months following article publication.
• IPD Sharing Access Criteria: Proposals should be directed to colleen.kelley@emory.edu. To gain access, data requestors will need to sign a data access agreement.
• IPD Sharing Supporting Information Type: Study Protocol

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No